We have investigated the transforming activities of the raf and myc oncogenes in hematopoetic and fibroblastic cells using a series of oncogene-transducing murine retroviruses. Fibrosarcomas and, to a lesser extent, erythroid hyperplasia are induced in newborn mice after a latency of 4-8 weeks by 3611 MSV, which contains the raf oncogene. In contrast, newly constructed myc oncogene-transducing murine retroviruses induce T-cell lymphomas after a 9-week latency. A combination of both oncogenes in an infectious murine retrovirus induces hematologic neoplasms 1-3 weeks after inoculation; these neoplasms consist primarily of immunoblastic lymphomas of both T- and B-cell lineage and erythroblastosis. Additionally, we have observed fibrosarcoma and adenocarcinoma of the pancreas, liver and lung. In parallel to the synergistic action of raf and myc oncogenes on hematopoetic and epithelial cell transformation in vivo, we find that raf-induced transformation of fibroblast cell lines in culture is enhanced by the addition of myc, which by itself only weakly morphologically transforms these permanent cell lines. Synergism between raf and myc has also been demonstrated in the immortalization of murine macrophages from fresh bone marrow and in the immortalization of growth factor-independent pre-B cell mast cells and myeloid stem cells derived from infected primary fetal liver cultures. The mechanisms underlying raf + myc synergism have been investigated in vitro. Cells from tumors induced by the myc or raf + myc transducing viruses can readily be established in culture in regular medium, whereas culture of cells from raf oncogene-induced tumors requires the addition of interleukin-3 (IL-3). A function for myc in this synergism has been indicated in studies involving infection of a series of IL-2 and IL-3-dependent cell lines with the various viruses. These studies have demonstrated that expression of high levels of v-myc alone can abrogate the growth factor requirements of these cell lines and probably functions in an analogous manner in its synergistic action with raf in the development of hematopoetic/lymphoid tumors in vivo.